(非常重要综述2010)CNS瘦素、胰岛素控制能量平衡的作用

Ann.N.Y.Acad.Sci.ISSN0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
Issue:The Year in Diabetes and Obesity
CNS leptin and insulin action in the control of energy homeostasis
Bengt F.Belgardt and Jens C.Br¨uning
Department of Mouse Genetics and Metabolism,Institute for Genetics,Center for Molecular Medicine,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases,Second Department for Internal Medicine University of Cologne,and Max Planck Institute for the Biology of Ageing,Cologne,Germany
Address for correspondence:Jens C.Br¨uning,M.D.,Institute for Genetics and Center for Molecular Medicine(CMMC), Department of Mouse Genetics and Metabolism,Z¨ulpicher Str.47a,50674Cologne,Germany.jens.bruening@uni-koeln.de The obesity and diabetes pandemics have made it an urgent necessity to define the central nervous system(CNS) pathways controlling body weight,energy expenditure,and fuel metabolism.The pancreatic hormone insulin and the adipose tissue–derived leptin are known to act on diverse neuronal circuits in the CNS to maintain body weight and metabolism in a variety of species,including humans.Because these homeostatic circuits are disrupted during the development of obesity,the pathomechanisms leading to CNS leptin and insulin resistance are a focal point of research.In this review,we summarize the recentfindings concerning the mechanisms and novel neuronal mediators of both insulin and leptin action in the CNS.
Keywords:obesity;leptin;insulin;central nervous system(CNS);pancreas;diabetes
Leptin and insulin as messengers of peripheral energy levels to the CNS
The circulating levels of leptin and insulin are pos-itively correlated with adiposity and body weight,1 and are now broadly accepted to deliver information on peripheral energy stores to the central nervous system(CNS)by acting on diverse neuron popu-lations.In line with this notion,intracerebroven-tricular(i.c.v.)injection of insulin or intranasal ap-plication of insulin,which selectively mirrors CNS insulin concentration,decreases food intake and body weight in mice,2rats,3baboons,4and men,5 although a recent report failed to detect an effect on food intake and body weight in rats.6Comparably stronger than insulin’s effect,leptin’s ability to re-duce food intake and decrease body weight is well established.7–9It has been ascertained that insulin and leptin action in the CNS,and here especially on neurons,is essential for decreasing the food intake (anorexigenic)and eventually weight reducing ef-fects of these two hormones,10,11although notably, the role of other cell types present in the CNS such as astrocytes or microglia,which do express insulin re-ceptors(IR)and leptin receptors(LEPR),12,13is still poorly understood in this regard.In addition to in-sulin’s critical roles in glucose and lipid metabolism in the periphery,leptin has also direct effects on pe-ripheral tissues,and the interested reader is directed to a recent review on this topic.14 Hypothalamic mediators of insulin
and leptin action
After the discovery that leptin and insulin mediate their effects on body weight and fuel metabolism by acting on neurons,the specific neuronal pop-ulation impacted on by both hormones had to be established.It was already known that in ro-dents,lesions in the hypothalamus could impact body weight,either inducing weight gain or weight loss,depending on the specific region of the hy-pothalamus ablated.In line with this,both lep-tin and IR are strongly and broadly expressed in the hypothalamus,insulin action in the hypothala-mus has been demonstrated to induce anorexia and weight loss,15whereas inhibition of insulin signal-ing has the opposite effect.16Similarly,hypothala-mic signaling is necessary for leptin’s effects on body weight.17,18
doi:10.1111/j.1749-6632.2010.05799.x
CNS leptin and insulin action Belgardt&Br¨uning Figure1.Circuitry of leptin and insulin responsive neurons.Neuron populations of the arcuate nucleus(ARC),ventromedial hypothalamus(VMH),paraventricular hypothalamus(PVH),lateral hypothalamus(LH),ventral tegmental area(VTA),raphe nucleus(RAPHE),and nucleus tractus solitarius(NTS)—which are responsive to leptin,insulin,or both—are depicted,as well as relevant synaptic contact between these neuron populations.POMC and AGRP neurons in the ARC arefirst-order neurons of both leptin and insulin.Whereas␥-aminobutric acid(GABA)released from AGRP neurons inhibits POMC neuron activation directly, POMC and AGRP neurons release␣-MSH and AGRP respectively onto PVH neurons,which express thyroid-releasing hormone (TRH)or corticotrophin-releasing hormone(CRH),which are involved in thermogenesis and feeding,respectively.In the VMH, steroidogenic factor1(SF1)expressing neurons are bonafide leptin-sensitive neurons,and predominantly regulate food intake.In the lateral hypothalamus,leptin acts on GABAergic neurons,which are in synaptic contact with dopaminergic neurons in the VTA. Both leptin and insulin also regulate activity of orexin neurons in the LH through hyperpolarization(leptin)or transcriptional repression of orexin(insulin).Dopaminergic neurons in the VTA,which release dopamine in the striatum to control activity and reward,are also directly silenced by leptin signaling,whereas dopamine reuptake is under control of insulin through transcriptional control of the dopamine transporter.Although serotonergic neurons in the raphe nucleus release serotonin(5-HT)onto POMC neurons in the ARC(and striatal neurons),leptin acts directly onto5-HT neurons as well.Finally,nucleus tractus solitarius(NTS) neurons relay and compute signals from the gastrointestinal(GI)tract and exchange information with the parabrachial nucleus (PBN).Additionally,GABA release in the PBN from AGRP neurons is essential for feeding.Note that some synaptic connections and target regions are not depicted for optimal clarity.Region descriptions are in bold and underlined,neuron descriptions are in bold,and neurotransmitters/neuropeptides are written in normal formatting.Leptin(L)or insulin(I)responsiveness is depicted in bold and italic.
Thefirst breakthrough in defining primary tar-get neurons of leptin and insulin occured in 2001,when it was demonstrated that proopiome-lanocortin(POMC)-expressing neurons are depo-larized by leptin treatment,which leads to an in-crease in neuronal activity.19In the hypothalamic melanocortin system,POMC-expressing neurons release the POMC cleavage product␣-melanocyte stimulating hormone(␣-MSH),which acts on downstream target neurons(some of which located in the paraventricular hypothalamus,Figure1)to reduce food intake,increase energy expenditure,
Belgardt &Br¨uning CNS leptin and insulin action
and regulate glucose metabolism.20–22In fact,null mutations in leptin,LEPR,POMC,its cleavage en-zymes (prohormone convertases),or downstream receptors (such as Melanocortin receptor 4,MC4R)relate to hyperphagia and obesity both in rodents and humans.23contrast to POMC neurons,acti-vation of arcuate nucleus (ARC)neurons coexpress-ing agouti-related protein (AGRP),and neuropep-tide Y (NPY)induces feeding,reduce energy expen-diture,and impacts on activity.24–26AGRP acts as an inverse agonist on the MC4R,whereas NPY reg-ulates neuronal activity by acting on several NPY receptors subtypes,ultimately blocking ␣-MSH-mediated anorexia.Of note,AGRP/NPY neurons also directly inhibit POMC neurons through synap-tic release of inhibitory ␥-aminobutric acid (GABA)on POMC soma.27The critical role of these two types of neurons has been demonstrated by acute ablation models,which lead to hyperphagia (POMC neuron ablation)or hypophagia (AGRP neuron ab-lation),and following these initial experiments,it was revealed that AGRP neuron-released GABA in the hindbrain parabrachial nucleus is necessary for feeding.25,26,28
With the advent of the Cre/loxP system,neuronal population-specific ablation of the IR or LEPR or their signaling components had been made possible,and mice with POMC or AGRP/NPY-specific abla-tion of these two receptors have been analyzed.Ab-lation of the leptin receptor in POMC,AGRP/NPY or both neurons led to elevated body weight and mild obesity,again underlining the role of the melanocortin pathway.29,30On the other hand,it was deducted from these experiments that there are other neuronal populations (and possibly extra-hypothalamic sites)that are critically targeted by leptin to inhibit feeding.
The ablation of IR from POMC and AGRP neu-rons surprisingly did not lead to hyperphagia or obe-sity,although IR signaling in AGRP neurons has an important role in systemic glucose metabolism (see below).31This was unexpected,because insulin’s anorexigenic action is at least partially dependent on an intact melanocortin system,32and insulin clearly regulates electrical activity and transcrip-tional events in POMC neurons,such as localization of forkhead transcription factors.33,34Several recent reports have further shed light on this notion.Both insulin and leptin were known to influence mem-brane polarization and firing only in a subset of
neurons,in the range of 50%of all POMC neurons tested,and in an opposite manner;whereas leptin depolarized POMC neurons,19insulin clearly hy-perpolarized POMC neurons.33,35This conundrum was elegantly resolved by the finding that these two hormones impact on different subpopulations of POMC neurons,that is there are neurons sensitive to leptin,whereas other neurons respond to insulin.36Moreover,combined leptin and insulin action in POMC neurons has synergistic effects on glucose homeostasis (and fertility),because mice lacking both IR and LEPR on POMC neurons show drastic impairment of steady state glucose metabolism.37Finally,it appears that in addition to the existence of subpopulations of POMC neurons with regard to receptor expression and hormone sensitivity,there are neurons which only shortly during development express POMC,some of which go on to express NPY during adulthood.38Nonetheless,in these neurons loxP-flanked genes of interest have already been re-combined due to the short-term activation of the POMC-Cre transgene,which may compromise the analysis of the resulting phenotype.Taken together,the efforts to unanimously identify the hypothala-mic neurons necessary for insulin-induced anorexia have proven fruitless so far,31with the primary lep-tin targets being better understood.
If hypothalamic insulin action is necessary and of consequence for food intake and body weight defense,of what nature are those neurons?First,there are several subhypothalamic nuclei,in which analysis of IR ablation has not been reported yet,for example the ventromedial and the paraventric-ular nuclei,which are insulin responsive and whose function is absolutely required for normal energy homeostasis.39–41Intriguingly,leptin signaling in ventromedial hypothalamic (VMH)or lateral hy-pothalamic (LH)neurons is of equal importance with regards to body weight control as is leptin signaling in POMC neurons.42,43The neuropep-tide orexin is in the LH,and it is cru-cial for wakefulness,mutations in orexin or its receptor are in narcolepsy in mice and men.44In the LH,leptin hyperpolarizes orexin-containing neurons,which is in line with the notion that satiety allows for periods of rest and sleep.45Similarly,a report found that insulin,through nuclear export of the transcription factor FOXA,decreases orexin expression,46whereas orexin application silences POMC neurons.47Besides these
CNS leptin and insulin action Belgardt&Br¨uning
targets,there are likely more hypothalamic neuron populations important for weight regulation,but there are no marker genes available yet to study them in detail.
In contrast,the role of hypothalamic insulin sig-naling in control of peripheral glucose metabolism is well established,48,49where electrical inhibition of neurons expressing AGRP has been identified as a major component of hepatic glucose production regulation likely through vagal innervations.31Lep-tin’s well-known ability to improve systemic glu-cose metabolism has also been shown to depend on hypothalamic circuits.50,51Indeed,there is now conclusive evidence that leptin signaling in POMC neurons is predominantly necessary for regulation of systemic glucose homeostasis.This notion was deducted from thefinding that reexpression of the LEPR only in POMC neurons,whereas all other cells lack the LEPR,was sufficient to mostly normal-ize glucose homeostasis(but not weight),whereas db/db mice(lacking LEPR globally)suffer from early onset uncontrolled diabetes.52
Notably,it has not yet been proven that CNS in-sulin and leptin action play the same role in humans, because patients undergoing liver transplantation and therefore hepatic deenervation show only mod-est changes in glucose production and metabolism, although thesefindings are hard to qualify due to the pathologies leading to the liver transplantation itself,immunosuppression therapy,and other en-docrine abnormalities detected after the transplan-tation.53Moreover,one group demonstrated that in dogs,CNS insulin action appears to have only a small effect on glucose metabolism,underlying the need for further studies in nonrodent species.54
In addition to glucose metabolism,both CNS in-sulin and leptin action has been demonstrated to regulate lipid uptake and/or metabolism in the white adipose tissue,highlighting the broad potency of these two hormones to coordinately orchestrate fuel partitioning.55–57
Leptin and insulin intracellular signaling cascades
Because leptin and insulin have profound effects on transcriptional and electrical events in neurons,the signaling events evoked by these hormones are of high interest(Figure2).Leptin activates intracel-lular signaling cascades through the recruitment of the Janus kinase(JAK)to the LEPR,where it phos-phorylates several key residues on the LEPR.Signal transducer and activator of transcription(STAT)3 proteins binds to the phosphorylated LEPR,and are themselves phosphorylated by JAKs.58This allows for dimerisation,and subsequent translocalization into the nucleus,where the STAT3proteins bind to and regulate transcription of target genes.24The role of this pathway especially in POMC transcription is well defined because leptin treatment increases POMC transcription.59On the other hand,leptin is able to stimulate the phosphatidylinositol-3-kinase (PI3K),which is also insulin’s main intracellular signaling cascade.60Here,insulin will stimulate binding of the regulatory subunit of the PI3K to phosphorylated insulin receptor substrates(IRS), which allows for activation of the catalytic subunit of the PI3K.PI3K catalyzes the phosphorylation of the membrane lipid phosphatidylinositol-4,5-bisphosphate(PIP2)and thus generates phosphatidylinositol-3,4,5-trisphosphate(PIP3). PIP3can bind to and activate ion channels,but is also recognized by phosphatidylinositol-dependent kinase1,which phosphorylates several proteins such as the kinase AKT to elicit downstream signaling events.61Although it is widely accepted that leptin activates PI3K signaling at least in specific neurons,the signaling cascade linking leptin stimulation to PI3K activation has not yet been fully resolved.Leptin action may also reduce the degradation of PIP3to PIP2by phosphorylation and thus deactivation of the PIP3dephosphatase phosphatase and tensin homologue(PTEN).62On the other hand,the adapter protein SH2B1has been shown to recruit JAK and IRS proteins in a su-percomplex,thus allowing crosstalk between these two pathways.63Importantly,SH2B1has also been linked to human obesity.64Leptin-induced PI3K signalling in the hypothalamus has been linked to peripheral glucose homeostasis and food intake,60,65 although the neuron populations mediating both effects are not completely elucidated.
Another molecular target of both leptin and in-sulin is the AMP-dependent kinase(AMPK).Low cellular energy levels will increase the AMP/ATP ra-tio,which is sensed by AMPK and converted into a cellular response to induce ATP generation and reduce ATP consumption.In the hypothalamus, AMPK activation increases food intake,and both leptin and insulin have been shown to decrease the phosphorylation and thus activation of AMPK in
Belgardt&Br¨uning CNS leptin and insulin
action
Figure2.Intracellular signaling cascades activated by insulin and leptin.Insulin and leptin are able to stimulate activity of the phosphatidylinositol-3-kinase(PI3K),which subsequently results in phosphorylation and nuclear exclusion of the forkhead transcription factors FOXO1and FOXA2.FOXO1is a negative regulator of carboxypeptidase E(CPE)expression in POMC neurons,whereas it stimulates transcription of AGRP in AGRP neurons.Leptin-activated STAT3binds to POMC and AGRP promoters,where it stimulates(POMC)or inhibits(AGRP)expression via recruitment of histone modifying enzymes.FOXA2was demonstrated to bind to the orexin and MCH promoters,where it stimulates expression of these neuropeptides.Insulin stimulation is known to increase expression of the dopamine transporter(DAT)gene in dopaminergic neurons.Both leptin and insulin are able to hyperpolarize neurons by PI3K-mediated opening of ATP-dependent potassium channels(K ATP channels)and subsequent potassium outflow.On the other hand,leptin is able to depolarize neurons and thus increase thefiring rate by opening a nonspecific cation channel by a PI3K and JAK-dependent pathway,and pharmacological manipulation has led to the conclusion that this channel may be the transient receptor potential(TRP)channel.Note that for clarity,several other pathways have been omitted(see text).
the hypothalamus,66although it is unresolved how exactly activation of AMPK is blocked by both hor-mones.AMPK action in POMC and AGRP neurons plays a role in the neuron’s response to ambient lev-els of glucose,whereas leptin’s and insulin’s effect on neuronfiring is not affected.67Besides these path-ways,leptin(and insulin)are able to induce mitogen-activated protein kinases(MAPK)such as extracellular signal-regulated kinase(ERK).Al-though ERK signaling mediates some of the effects of leptin on food intake in the hypothalamus,68it is unknown if insulin uses this pathway to maintain body weight.
Transcription,membrane potential,
and synaptology
As true regulators of neuronal activity,leptin and in-sulin change membrane potential of target neurons
CNS leptin and insulin action Belgardt&Br¨uning
to controlfiring rate and thus neuropeptide and neurotransmitter release.Both leptin’s and insulin’s effect on POMC neuronfiring has been extensively studied,with leptin depolarizing and insulin hyper-polarizing a subset of POMC neurons.With regards to leptin,the cation-channel opened by leptin stim-ulation has been elusive for some years,with recent reports implicating both leptin-stimulated JAK and especially PI3K signaling in opening of transient re-ceptor potential channels in POMC neurons,and it will be highly informative to see if this holds true also for other leptin-stimulated neurons,such as VMH neurons.69,70On the other hand,both in-sulin and leptin have been shown to be able to ac-tivate ATP-dependent potassium(K ATP)channels, which leads to potassium outflow,hyperpolariza-tion and a reduction of thefiring rate.71,72This has been well demonstrated for AGRP neurons.31,73,74 Mechanistically,it has been proposed that PI3K ac-tivation leads to local accumulation of PIP3,which binds to K ATP channels,increasing the probability for an“open”channel,and reducing the affinity for ATP.75On the other hand,PIP3generation alone may not be sufficient,because actinfilament sta-bilization prevents insulin-stimulated K ATP channel opening,whereas the mechanisms induced by in-sulin(and leptin)to control actinfilament dynam-ics are poorly understood.74As the name suggests, K ATP channels are sensitive to cellular levels of ATP, that is,they are closed by intracellular rises in ATP. Glucose-sensitive neurons(such as POMC neurons) are able to sense a rise in ambient glucose concentra-tions,because the increase in cytoplasmic ATP in re-sponse to glycolysis closes the K ATP channels,which eventually results in depolarization and an increase infiring rate.76PI3K activation and insulin stimu-lation have also been reported to depolarize AGRP neurons,although the channels involved have not been identified,underscoring the diversity offind-ings regarding electrophysiological responses to in-sulin and leptin,as recently discussed.67,76,77Taken together,depending on the neuronal population, acute insulin and leptin application may depolar-ize or hyperpolarize target neurons,effects which may be accounted for by differential expression of their receptors,that of ion channels or intracellular signaling intermediates determining the net result. Both leptin and insulin directly control transcrip-tion of target genes,including neuropeptides.As mentioned before,leptin-activated STAT3signaling controls POMC transcription in POMC neurons.59 In the same vein,leptin and insulin stimulation leads to phosphorylation and nuclear exclusion of the forkhead transcription factor FOXO1,allowing for STAT3binding to the promoter and transcrip-tion of POMC.33,34,78,79FOXO1is also a negative regulator of carboxypeptidase E(CPE)expression, which is important for a distal step in processing POMC into its cleavage products,i.e.,␣-MSH.80 Regarding expression of orexigenic neuropep-tides,FOXO1and STAT3again compete for binding to the promoters of AGRP and NPY,with FOXO1 being an activator of transcription of these orexi-genic neuropetides,and STAT3being inhibitory.78,79 Indeed,leptin’s ability to reduce AGRP/NPY ex-pression depends on PI3K signaling,81and insulin stimulation excludes FOXO1from the nucleus of AGRP neurons.34Because mice with constitutive STAT3activation only in AGRP neurons are hyper-active and lean,STAT3signaling in these neurons surprisingly regulates locomotor activity,although the downstream neurons mediating this phenotype are unknown.24Interestingly,mice with constitutive STAT3signaling in POMC neurons are hyperphagic and mildly obese,due to suppressor of cytokine sig-naling(SOCS)3overexpression.82SOCS3inhibits activation of the leptin signaling cascade at the level of the receptor,and SOCS3expression is under con-trol of STAT3signaling,thus constituting a negative feedback loop.Because leptin levels are chronically elevated in obesity,SOCS3levels are increased in the hypothalamus of obese mice,83and ablation of SOCS3in the brain or POMC neurons ameliorates high fat diet-(HFD)induced obesity.84,85Nonethe-less,hyperleptinemia alone does not induce SOCS3-mediated leptin resistance and consequently obesity,because leptin-transgenic mice remain leptin sensitive.86Interestingly though,hyper-leptinemia predisposed leptin-transgenic mice to obesity when challenged with a HFD.SOCS3is also an inhibitor of insulin signaling through degrada-tion of IRS proteins,thus(at least in POMC neu-rons)hyperleptinemia or STAT3overactivation will concurrently lead to cellular insulin resistance.82,87 Leptin also controls expression of multiple neu-ropeptides in neurons downstream of POMC and AGRP/NPY neurons,for example in the paraven-tricular neurons(PVN).Here,leptin has been shown to increase expression of thyroid releas-ing hormone(TRH),which is a positive regulator
Belgardt&Br¨uning CNS leptin and insulin action
of energy expenditure.88Moreover,leptin stimu-lation affects transcription of many more genes, nonetheless mice with leptin receptor deficiency only in the PVN have not been generated yet,thus the direct and indirect targets(through neuropep-tide/neurotransmitters released by upstream neu-rons)are currently indistinguishable.89
Besides direct transcriptional control and mem-brane potential regulation,leptin(and purport-edly insulin)signaling is able to change the synaptic input onto neurons.For example,mice lacking leptin show decreased numbers of gluta-matergic(=excitatory)synapses on POMC neurons and increased glutamatergic input on NPY neurons, both of which is rapidly,that is in hours,normal-ized upon leptin treatment.90Other hormones,for example estrogen,a known anorexigenic hormone, or ghrelin,which stimulates food intake,also regu-late synaptic input,90,91thus synaptic rewiring may be an important level of regulation used by many different hormones involved in energy homeostasis. Nonetheless,it is still unresolved by which mech-anism and which attractant the synapses are re-cruited or repelled,and,if this is due to signaling on the presynaptic or postsynaptic neurons.Although a role for insulin in synaptic plasticity in neurons directly linked to energy homeostasis has not been reported,postsynaptic insulin action in hippocam-pal neurons is known to recruit GABA receptors and thus sensitize cells for this inhibitory neurotransmit-ter,92which at least opens up the question if insulin plays a similar role in hypothalamic neurons. Extrahypothalamic neurons targeted
by insulin and leptin
Clear evidence that hypothalamic neurons do not contribute all of the weight-regulating effects of both leptin and insulin has opened the search for other nuclei expressing LEPR and IR,and analysis of their importance with regards to energy homeostasis.All of these nuclei and neuropeptide circuits had been previously shown to control body weight regula-tion,and it is now obvious that insulin and leptin act on almost all levels of feeding,including food recognition,food liking,and meal initiation. Dopamine
The generation of mice lacking dopamine in the brain led to the discovery that these mice show re-duced activity,less food intake,and would die if not treated with l-dopa,which is metabolized to dopamine.93Notably,if these mice are crossed to mice lacking leptin,the resulting animals are also hypophagic and die.94The role of the dopaminer-gic circuit concerning addiction to drugs such as alcohol,amphetamines or cocaine but also to the rewarding aspect of food is well established,95with dopaminergic neurons located in the substantia ni-gra(SN)and ventral tegmental area(VTA)pro-jecting to many brain nuclei involved in activity, decision-making and activity,such as the frontal cortex,hippocampus or the striatum.Intriguingly, there is now growing evidence that obesity is also linked to dysfunction of the dopaminergic system, as striatal dopamine D2receptor binding is reduced in obese patients as measured by positron emis-sion tomography.96Most importantly,leptin and insulin impact on midbrain dopaminergic neurons to regulate food-finding behavior and eventually body weight.95Thus,LEPR are expressed on VTA dopaminergic neurons,which are hyperpolarized after stimulation with leptin ex vivo.97,98Moreover, leptin microinjection into the VTA reduces food intake,whereas ablation of the receptor only in the VTA increased the sensitivity of these mice to the rewarding aspect of highly palatable food,such as sucrose.98The crucial role for VTA dopamine neurons in the regulation of energy homeostasis is underlined by thefinding that direct leptin ac-tion on LH neurons also signals to VTA dopamine neurons by synaptic contact,decreasing food in-take and thus body weight.43Besides LEPR,the IR is also expressed on VTA(and SN)dopaminer-gic neurons.99Intracerebroventricular insulin treat-ment has been demonstrated to increase expression the dopamine transporter(DAT)in dopaminergic neurons.100Dopamine from the synaptic cleft is taken up by DAT back into the presynaptic neu-ron,and thus stops to stimulate postsynaptic neu-rons.Hence,insulin may act through this cascade to decrease the rewarding effect of food,which is in line with thefindings from multiple experimental paradigms.95
Serotonin
In the CNS,serotonin(5-Hydroxytryptamin)is a neuropeptide expressed only in the raphe nucleus located in the midbrain.Besides being involved in mood regulation,serotonin clearly plays an impor-tant role in the control of weight.Thus,molecules。